Allergic Reaction to Vanadium Causes a Diffuse Eczematous Eruption and Titanium Alloy Orthopedic Implant Failure

CONTACT DERMATITIS

Sally Engelhart, BA; Robert J. Segal, MD

PRACTICE POINTS • Vanadium may be an underrecognized allergen in patients with metalcopy implants. • Consider vanadium allergy in those with surgical implants and signs of hypersensitivity reaction. • Test for allergy with vanadium trichloride. • Niobium is an alternative for implants in vanadium-allergic patients. not

Allergy as a cause of adverse outcomesDo in their different microstructures, contributing to patients with implanted orthopedic hardware is the release of vanadium in vivo. The patient was controversial. Allergy to titanium-based implants patch tested with several metals including com- has not been well researched, as titanium is tradi- ponents of the implant and had a positive patch tionally thought to be inert. We highlight the case test reaction only to vanadium trichloride. These of a patient who developed systemic dermatitis findings support a diagnosis of vanadium allergy and implant failure after surgical placement of a and suggests that clinicians should consider titanium alloy (Ti6Al4V) plate in the left foot. The including vanadium when patch testing patients hardware was removed andCUTIS the eruption cleared with a suspected allergic reaction to vanadium- in the following weeks. The plate and screws containing implants. were submitted for metal analysis. The elemental Cutis. 2017;99:245-249. composition of both the plate and screws included 3 major elements—titanium, aluminum, and vanadium—as well as trace elements. Metal anal- etal allergy in patients with orthopedic ysis revealed that the plate and screws had differ- implants can cause serious problems includ- ent microstructures, and electrochemical studies Ming dermatitis and implant failure.1 As life demonstrated that galvanic corrosion could have expectancy increases, the general population ages, occurred between the plate and screws due to and more metallic orthopedic implants are placed,2 allergy to these implants is expected to be a problem of greater significance. Uncertainty remains regard- Ms. Engelhart is from Harvard Medical School, Boston, ing best practice for patients with suspected metal Massachusetts. Dr. Segal is from the Division of Dermatology, implant allergy.1 The major questions are: Who University of Arizona, Tucson. should be tested? When should they be tested? What The authors report no conflict of interest. 3-8 Correspondence: Robert J. Segal, MD, Division of Dermatology, are the optimal tests to diagnose metal allergy? University of Arizona, 3838 N Campbell Ave, Tucson, AZ 85719 We report the case of a patient with vana- ([email protected]). dium allergy who developed a diffuse eczematous

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dermatitis and implant failure after receiving a The patient had persistent pain and swelling vanadium-containing titanium alloy orthopedic at the surgical site, and radiographs taken post- implant in the left foot. This case is remarkable operatively at 6 months showed implant failure because hypersensitivity reactions to titanium-based (Figure 3). The hardware was surgically removed hardware are rare, as they traditionally have not 8 months after implantation (Figure 4) and the been thought to provoke allergic reactions.9 plate and screws were submitted to the Institute for Mineral Resources Geosciences LA-ICP-MS Facility Case Report and the Lunar and Planetary Laboratory at the A 62-year-old woman who was otherwise healthy University of Arizona (Tucson, Arizona) for analy- presented with an eruption of more than 80 pruritic, sis. The skin lesions began to improve days after the nummular, eczematous plaques on the arms, legs, hardware was removed and the eruption cleared over back, and buttocks of 3 weeks’ duration (Figure 1). the following 3 weeks with no additional treatment. She had a history of allergy to metal used in costume After the hardware was removed, it was analyzed jewelry. Six weeks prior, the patient underwent to determine the elemental composition of the plate implantation of a titanium alloy plate in the left and screws, and the patient was then patch tested foot for surgical repair of painful deforming osteo- with the major metal components of the implant: arthritis. A radiograph of the foot showed appro- aluminum chloride hexahydrate 2.0% pet, elemental priate placement. According to the manufacturer, titanium 10.0% pet, titanium dioxide 10.0% pet, the plate was composed of the compound Ti6Al4V, titanium (III) nitride 5.0% pet, titanium (III) oxalate which contained 90% titanium, 6% aluminum, and 4% vanadium. The lesions developed on the skin close to but not directly over the surgical site. copy A punch biopsy of one of the lesions on the shoulder showed lymphoeosinophilic spongiosis consistent with a delayed hypersensitivity reaction (Figure 2). There was mild clinical improvement of not the eruption with topical steroids. A course of pred- nisone for systemic effect resulted in clearing of the eruption, but it promptly recurred on cessation of the steroids. The patient was then patch tested usingDo the North American 80 Comprehensive Series, with an additional 59 common textile, shampoo, fragrance, and several metal allergens, all of which were negative. A CUTIS

Figure 2. Vanadium allergy histopathology from a punch A B biopsy of a lesion showing lymphoeosinophilic spongiosis (A) and numerous eosinophils (B)(H&E, original Figure 1. Vanadium allergy with eczematous plaques on magnifications ×10 and ×40). Photographs courtesy of the left leg (A) and right thigh (B). Keliegh Culpepper, MD (Tucson, Arizona).

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decahydrate 5.0% pet, elemental vanadium 5.0% pet, and vanadium (III) chloride 1.0% pet. She demon- Table 1. strated a 1+ reaction (erythema and induration) to Major Components Determined by vanadium trichloride at 72 and 96 hours. The plate and screws removed from the patient Electron Microprobe Analysis were sterilized and submitted for analysis. Electron Plate, Screws, microprobe analysis confirmed that the major ele- Metal wt/wt wt/wt mental composition of the plate and screws essen- tially matched the manufacturer’s listing (Table 1). Titanium 90.005 90.260 The trace elements were determined using laser abla- Aluminum 6.243 6.348 tive inductively coupled mass spectroscopy, which Vanadium 4.025 3.829 demonstrated that the screws were of different metal composition from the plate (Table 2). Electron microprobe analysis also was used to determine the microstructure of the plate and screws. The plate had referred to simply as titanium, but the distinction is 2 distinct phases consisting of a titanium-aluminum important when it comes to medical implants and phase and a vanadium phase, whereas the screw was devices. Commercially pure titanium is more than much more homogeneous. Basic electrochemical 99% pure titanium, but up to 1% of its volume can studies were performed in a salt solution replicat- be comprised of impurities.10 In titanium alloys, ing the tissue of the foot. These studies showed that the alloy elements are intentionally added to cre- galvanic corrosion could have occurred between the ate a material with optimal properties. The 2 most plate and screws due to the differences of composition. common types copyof titanium that are used for orthopedic implants are cp-Ti and Ti6Al4V, a titanium Comment alloy containing approximately 90% titanium, Titanium is an attractive metal to use in orthopedic 6% aluminum, and 4% vanadium. Similar to cp-Ti, implants. It has a high strength-to-weight ratio, a titaniumnot alloys also can contain impurities such as low modulus of elasticity, and good resistance to cor- aluminum, beryllium, cobalt, chromium, iron, nickel, rosion. Titanium can be categorized as either com- and palladium, among many others. Although these mercially pure titanium (cp-Ti) or a titanium alloy. impurities often are considered negligible from a Colloquially, both cp-Ti and titanium alloys are oftenDo metallurgy perspective, as they do not change the

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Figure 3. Radiograph of the left foot prior to removal of Figure 4. Surgical hardware containing vanadium the implant showed implant failure due to vana- after removal from a patient who demonstrated an aller- dium allergy. gic reaction.

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Vanadium is known to be allergenic, especially Table 2. in the presence of implant failure.12,13 In our patient, Trace Elements Determined by patch testing with more than 100 allergens was negative, except for vanadium trichloride 1%. Our Laser Ablative Inductively Coupled patient’s presentation strongly suggested that she Mass Spectroscopy developed a vanadium allergy manifesting as systemic allergic contact dermatitis. She demonstrated Element Plate, ppm Screws, ppm no history of skin disease, a widespread eczema- Silicon 1739.000 2497.000 tous eruption after exposure, histology consistent Iron 1741.834 1857.000 with systemic contact allergy, a positive patch test Sulfur 309.533 686.489 to vanadium, and clearance of the eruption on removal of the antigen, which have been proposed Nickel 89.860 107.200 as objective criteria that support a diagnosis of metal Chromium 152.800 80.373 implant allergy.14 She refused our suggestion to reim- Zinc 36.968 46.310 plant a portion of the remaining plate under the Copper 34.570 42.640 skin without screws and monitor for recurrence of Molybdenum 5.680 32.090 the eruption. She did not have a lesion overlying the surgical site, but she did develop lesions near the Tin 3.727 25.890 surgical scar. The literature indicates that cutaneous Arsenic 5.201 24.980 manifestations of allergy to metallic implants can be Phosphorus 11.110 18.887 both localized and generalized.14 Zirconium 5.514 16.180 Although reportscopy are rare, other researchers have Niobium 4.654 11.690 found vanadium allergy in patients with metal orthopedic implants.5,12,13,15 The scarcity of literature on Gallium 8.079 9.400 vanadium allergy seems to suggest that it is a rare Tungsten 0.457 6.796 entity,not but we believe that it may be more common. Cobalt 3.202 5.098 Vanadium allergy may be underdiagnosed because it Manganese 32.640 3.936 is not a standard patch test allergen. Furthermore, many of those who do choose to test for it use what Lead 0.278 0.764 Dowe believe to be ineffective formulas of vanadium Tantalum 0.224 0.424 when patch testing patients. Our patient demon- Hafnium 0.126 0.156 strated a positive patch test reaction only to vana- Scandium 0.094 0.087 dium trichloride and not to pure vanadium, which Uranium 0.048 0.064 is consistent with the small number of other studies that investigated vanadium allergy.5,12,13,15 We believe Thorium 0.047 0.011 that vanadium trichloride is more water soluble than elemental vanadium,16 and thus more likely to iden- CUTIS tify true vanadium allergy than other test materials. Although reports of vanadium allergy in patients properties of the material, these trace elements may with metal implants are rare in the medical litera- be present in large enough quantities to cause hyper- ture, the material science literature clearly states that sensitivity reactions.11 vanadium is toxic and that vanadium-containing Several weeks after implantation of a titanium implants are problematic.17-20 It has been shown that alloy metal plate in the left foot, a widespread although Ti6Al4V implants are considered highly eczematous eruption developed in our patient who resistant to corrosion, they will slowly and con- had no prior skin disease. The eruption was steroid tinuously corrode in a physiologic environment responsive but did not clear until the plate was and release titanium, aluminum, and vanadium removed. Detailed metallurgy analysis confirmed ions, both systemically and into the peri-implant that vanadium was present and was not homoge- space.11 To address these problems with vanadium, neously distributed in the plate. The plate also vanadium-free titanium alloys such as Ti6Al7Nb was different in composition from the screws. have specifically been developed for medical use Additional studies showed that galvanic corrosion to address the problems caused by vanadium. between the plate and the chemically different Ti6Al7Nb contains 7% niobium rather than vana- screws might have contributed to the release of vanadium and appears to have some improved qualities dium in the tissue. in surgical implants.17

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There is still a great deal of uncertainty around 8. Amini M, Mayes WH, Tzeng TH, et al. Evaluation and metal implant allergy. Allergy to metal implants can management of metal hypersensitivity in total joint be difficult to diagnose for several reasons. Some arthroplasty: a systematic review. J Long Term Eff Med metals are not conducive to patch testing because Implants. 2014;24:25-36. of their low bioavailability. Additionally, we lack 9. Thomas P, Bandl WD, Maier S, et al. Hypersensitivity to validated and standardized patch test formulas for titanium osteosynthesis with impaired fracture healing, metals that can be diagnosed by patch testing. eczema, and T-cell hyperresponsiveness in vitro: case Furthermore, there is uncertainty about what to do report and review of the literature. Contact Dermatitis. after allergy to a metal implant is diagnosed; in some 2006;55:199-202. cases (eg, with more extensive procedures such as 10. Wood MM, Warshaw EM. Hypersensitivity reactions total joint replacements), removal or replacement of to titanium: diagnosis and management. Dermatitis. the implant may be associated with increased risk of 2015;26:7-25. further complications.6,21 11. Cadosch D, Chan E, Gautschi OP, et al. Metal is not inert: role of metal ions released by biocorrosion in Conclusion aseptic loosening—current concepts. J Biomed Mater Res We suggest that manufacturers consider vanadium- A. 2009;91:1252-1262. free alloys such as Ti7Al6Nb, which contains niobium 12. Granchi D, Cenni E, Trisolino G, et al. Sensitivity instead of vanadium, in their surgical implants,22 and to implant materials in patients undergoing total hip if surgeons have a choice, they should consider using replacement. J Biomed Mater Res B Appl Biomater. titanium implants with niobium rather than vana- 2006;77:257-264. dium.10 We suggest that clinicians consider vanadium 13. Granchi D, Cenni E, Tigani D, et al. Sensitivity to implant allergy in patients with Ti6Al4V surgical implants materials in copypatients with total knee arthroplasties. and signs of a hypersensitivity reaction, and include Biomaterials. 2008;29:1494-1500. vanadium trichloride 1% when patch testing. 14. Thyssen JP, Menné T, Schalock PC, et al. Pragmatic approach to the clinical work-up of patients Acknowledgment—The authors would like to thank notwith putative allergic disease to metallic orthopae- Nicholas R. Krasnow, PhD (Tucson, Arizona), for dic implants before and after surgery. Br J Dermatol. his invaluable help coordinating, performing, and 2011;164:473-478. interpreting the metal analyses. 15. Krecisz B, Kie´c-S´ wierczynska M, Bakowicz-Mitura K. Do Allergy to metals as a cause of orthopedic implant REFERENCES failure. Int J Occup Med Environ Health. 2006; 1. Basko-Plluska JL, Thyssen JP, Schalock PC. Cutane- 19:178-180. ous and systemic hypersensitivity reactions to metallic 16. Costigan M, Cary R, Dobson S. Vanadium Pentoxide implants. Dermatitis. 2011;22:65-79. and Other Inorganic Vanadium Compounds. Geneva, 2. Kurtz S, Ong K, Lau E, et al. Projections of primary Switzerland: World Health Organization; 2001. and revision hip and knee arthroplasty in the United 17. Challa VS, Mali S, Misra RD. Reduced toxicity and States from 2005 to 2030. J Bone Joint Surg Am. superior cellular response of preosteoblasts to Ti-6Al-7Nb 2007;89:780-785. CUTIS alloy and comparison with Ti-6Al-4V. J Biomed Mater Res 3. Thyssen JP, Johansen JD, Menné T, et al. Hypersensitiv- A. 2013;101:2083-2089. ity reactions from metallic implants: a future challenge 18. Okazaki Y, Rao S, Ito Y, et al. Corrosion resistance, that needs to be addressed. Br J Dermatol. 2010; mechanical properties, corrosion fatigue strength and 162:235-236. cytocompatibility of new Ti alloys without Al and V. 4. Aquino M, Mucci T. Systemic contact dermatitis and Biomaterials. 1998;19:1197-1215. allergy to biomedical devices. Curr Allergy Asthma Rep. 19. Paszenda Z, Walke W, Jadacka S. Electrochemical investi- 2013;13:518-527. gations of Ti6Al4V and Ti6Al7Nb alloys used on implants 5. Krecisz B, Kiec-Swierczynska M, Chomiczewska-Skora in bone surgery. J Achievements Materials Manufacturing D. Allergy to orthopedic metal implants—a prospective Eng. 2010;38:24-32. study. Int J Occup Med Environ Health. 2012;25:463-469. 20. Wang K. The use of titanium for medical applications in 6. Atanaskova Mesinkovska N, Tellez A, Molina L, et al. the USA. Materials Sci Eng A. 1996:134-137. The effect of patch testing on surgical practices and 21. Haseeb M, Butt MF, Altaf T, et al. Indications of implant outcomes in orthopedic patients with metal implants. removal: a study of 83 cases. Int J Health Sci (Qassim). Arch Dermatol. 2012;148:687-693. 2017;11:1-7. 7. Frigerio E, Pigatto PD, Guzzi G, et al. Metal sensitivity in 22. Geetha M, Singh AK, Asokamani R, et al. Ti based bio- patients with orthopaedic implants: a prospective study. materials, the ultimate choice for orthopaedic implants— Contact Dermatitis. 2011;64:273-279. a review. Progress Materials Sci. 2009;54:397-425.

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